As part of last cycle's previous Aim lb of this Autoimmunity Program Project, we cloned a novel Th 1-specific negative receptor that we call BTLA, for B and T Lymphocyte Attenuator. BTLA appears to belong to the CD28/B7 Ig superfamily. Preliminary data for BTLA substantiates a role in regulating terminal effector Th1 responses and autoimmunity: 1) BTLA is expressed exclusively within the lymphoid compartment, expressed by Th1 T cells and B cells. 2) BTLA has similar domain structure to CD28, ICOS, CTLA-4 and PD-1, is glycosolated transmembrane surface protein with conserved tyrosine signaling motifs that become phosphorylated. 3) BTLA expression appears regulated between cell surface and intracellular stores, influenced by its cytoplasmic and Ig domains, reminiscent of surface regulation of CTLA-4. 4) We already have made BTLA-/-mice, which show increased susceptibility to experimental allergic encephalitis (EAE). BTLA-/- T cells show increased proliferation to antigen presented by dendritic ceils. 5) Using a BTLA-Ig fusion protein, we found evidence for a BTLA ligand expressed by CD11c+ dendritic cells (DC), and show that this interaction exerts an inhibitory effect on Th1 proliferation with DC as antigen presenting cells. Our hypothesis is that BTLA is a new T cell inhibitory receptor of the CD28/B7 superfamily. This application focuses on a full characterization of BTLA biology. Aim 1 will examine BTLA gene and protein regulation and signaling properties. Aim 2 will use our BTLA-deficient mouse model to perform a systematic analysis of several distinct autoimmune model systems, chosen for their dependence upon Th1 pathogenic T cells. Aim 3 proposes to clone the BTLA ligand that we identify as expressed by dendritic cells. Identification of the BTLA ligand will be important in understanding and extending the biology of BTLA in autoimmune processes. These findings are highly significant, since BTLA is highly conserved in mouse, rat and human, thus has potentially conserved role in regulating human T cell responses impacting autoimmune diseases.